Heart failure continues to be a major public health problem in our society. Clinical and experimental studies have shown that female gender is associated with improved prognosis in heart failure, but the mechanisms underlying the gender based differences in heart failure survival are not known. Recent data show that female gender is associated with decreased cardiomyocyte apoptosis in normal and failing hearts, providing a plausible explanation for gender differences in heart failure progression. Whether sex hormones influence cardiomyocyte survival in failing hearts ha not been studied. Over the past several years, our lab has explored the effects of 17beta-estradiol (E2), the primary circulating form of estrogen, in cardiomyocyte signaling. In a mouse model of myocardial infarction, we reported that physiologic E2 replacement administered to ovariectomized females reduced infarct size and cardiomyocyte apoptosis in the peri-infarct zone, in association with heightened myocardial activation of the serine-threonine kinase Akt that has important anti-apoptotic effects in cells. In cultured cardiomyocytes, physiologic levels of E2 inhibit anthracycline-induced apoptosis by estrogen receptor (ER) - and phosphoinositide-3 (PI3) kinase/Akt-dependent mechanisms. Moreover, within cardiomyocytes, E2 induces the formation of a signaling complex that contains Estrogen Receptor a, cSrc-kinase, the p85 regulatory subunit of PI3 kinase, and Striatin, a membrane-associated scaffold protein. Based on these exciting new data, we hypothesize that estrogen-mediated cardiomyocyte protection occurs via ER-dependent activation of the PIS kinase-Akt signaling pathway that leads to inhibition of cardiomyocyte apoptosis. This hypothesis will be tested with three Specific Aims: SA#1: Explore the contribution of both estrogen receptors alpha and beta, and the PI3 kinase signaling pathway in estrogen-mediated cardiomyocyte protection in vivo, SA#2: Examine the mechanisms of estrogen-mediated cardiomyocyte protection in vitro by analyzing the specific contributions of ERalpha, ERbeta, and components of the PI3 kinase-Akt signaling pathway. SA#3: Investigate the molecular mechanisms of estrogen receptor-dependent PI3 kinase and Akt activation in cardiomyocytes. These experiments will help elucidate the molecular basis for estrogen/estrogen receptor-dependent cardiomyocyte protection. Completion of these studies will add to our understanding of the gender-based differences in cardiomyocyte apoptosis and heart failure progression, and the role of sex hormones in ischemic heart disease and heart failure which are major causes of morbidity and mortality in our society.